The present invention relates to a process for preparing substituted hydroxypyrazoles, and also to novel intermediates. Lower 1-alkyl-5-hydroxypyrazoles are known compounds which are used as intermediates for active compounds in agrochemicals, in particular for preparing herbicides (see WO 97/23135, WO 97/19087, U.S. Pat. No. 5,631,210, WO 97/12885, WO 97/08164, ZA 9510980A, WO 97/01550, WO 96/31507, WO 96/30368, WO 96/25412).
As processes for preparing lower 1-alkyl-5-hydroxypyrazoles the following syntheses are known:
1. A preparation in which
2-methyl-1-(p-toluenesulfonyl)-3-pyrazolidone or
2-methyl-1-acetylpyrazolidone is hydrolyzed (J. Prakt. Chem. 1971, 313, 115-128 and J. Prakt. Chem. 1971, 313, 1118-1124);
2. A variant in which an alkyl ester of
5-hydroxy-1-alkylpyrazole-4-carboxylic acid is built up by cyclizing a dialkyl alkoxymethylenemalonate using lower alkylhydrazines, subsequently adding an aqueous mineral acid solution to this reaction product and carrying out the hydrolysis and decarboxylation simultaneously (see JP 61257974, JP 60051175, JP 58174369, JP 58140073 and JP 58140074 and also U.S. Pat. No. 4,643,757);
3. A synthesis in which ethyl propiolate is reacted with methylhydrazine to form 5-hydroxy-1-methylpyrazole (Annalen 1965, 686, 134-144);
4. A synthetic route in which 3-hydrazinopropionic esters formed by addition of hydrazine onto acrylic esters are reacted with aldehydes to give the corresponding hydrazones and are subsequently cyclized (see JP 06166666, JP 61229852 and JP 61268659 and also EP 240001);
5. A synthetic variant in which
5-hydroxy-1-methylpyrazole-3-carboxylic acid is dissociated thermally (Chem. Ber. 1976, 109, p. 261);
6. A process in which 3-alkoxyacrylic esters are reacted with methylhydrazine to give 1-methyl-5-hydroxypyrazole (see JP 189 271/86).
The above-described syntheses have various disadvantages:
In the 1st synthetic route mentioned above, the process has a plurality of stages and is complicated. The insertion and removal of a protective group is cumbersome, results in additional steps and reduces the yield.
The 2nd method of preparation has a plurality of stages and, in addition, forms not only the 1-alkyl-5-hydroxypyrazoles but at the same time also the regioisomeric 1-alkyl-3-hydroxypyrazoles which have to be separated from the target compounds at some cost. Furthermore, the synthesis gives a poor C yield since use is made of a C4 building block from which a C atom has to be removed again at the end of the process.
In the 3rd synthetic variant, which describes only the preparation of 1-methyl-5-hydroxypyrazole, the use of amounts of methylhydrazine far above the stoichiometric amount is indispensable, thus making the process uneconomical. In addition, the 3-hydroxy-1-methylpyrazole which is likewise formed has to be removed at some cost from the 1-methyl-5-hydroxypyrazole during the purification. Furthermore, this process is uneconomical because of the high price of the propiolic ester.
In the 4th alternative, the process has a plurality of stages and is complicated. The last step of the complicated process gives only poor yields and many by-products.
In the 5th synthetic route, a high temperature is necessary for the thermal dissociation and the yield of 6% is very low.
In the 6th method of synthesis, which describes only the preparation of 1-methyl-5-hydroxypyrazole, use is made of 3-alkoxyacrylic esters which are cumbersome to prepare and expensive. 3-alkoxyacrylic esters are prepared by reaction of methanol with expensive propiolic esters (Tetrahedron Lett. 1983, 24, 5209, J. Org. Chem. 1980, 45, 48, Chem. Ber. 1966, 99, 450, Chem. Lett. 1996, 9, 727-728), by reaction of expensive and difficult-to-synthesize xcex1,xcex1-dichloro(diethyl ether) with bromoacetic esters (Zh. Org. Khim. 1986, 22, 738), by reaction of bromoacetic esters with trialkyl formates (Bull. Soc. Chim. France 1983, N 1-2, 41-45) and by elimination of methanol from 3,3-dialkoxypropionic esters (DE 3701113) (obtainable by reaction of the expensive methyl propiolate with methanol (J. Org. Chem. 45 1976, 41, 3765), by reaction of 3-N-acetyl-N-alkyl-3-methoxypropionic esters with methanol (J. Org. Chem. 1985, 50, 4157-4160, JP 60-156643), by reaction of acrylic esters with alkylamines and acetic anhydride (J. Org. Chem. 1985, 50, 4157-4160), by reaction of ketene with trialkyl orthoformate (DK 158462), by palladium- and simultaneously copper-catalyzed reaction of acrylic esters with methanol (DE 4100178.8), by reaction of trichloroacetyl chloride with vinyl ethyl ether (Synthesis 1988, 4, 274), by reaction of xcex1,xcex1,xcex1-trichloro-xcex2-methoxybuten-2-one with methanol (Synthesis 1988,4, 274) and by reaction of the sodium salts of 3-hydroxyacrylic esters with alcohols (DE 3641605)). The poor accessibility of the 3-alkoxyacrylic esters therefore makes the synthesis by the 6th route uneconomical. Furthermore, JP 189 271/86 describes the isolation of 5-hydroxy-1-methylpyrazole as hydrochloride but gives no information on the isolation and purification of the free base. If an attempt is made to employ the reaction conditions described in JP 189 271/86 and to isolate the free base, only very small yields which are uneconomical for an industrial-scale preparation of hydroxypyrazoles are obtained.
Consequently, these synthetic routes cannot be considered to be economical and efficient processes for preparing 1-alkyl-5-hydroxypyrazoles. This applies particularly to the industrial preparation of 1-alkyl-5-hydroxypyrazoles in large quantities.
It is an object of the present invention to provide an alternative process for preparing 1-alkyl-5-hydroxypyrazoles which does not have the abovementioned disadvantages of the previously known preparative methods.
We have found that this object is achieved by the process of the present invention.
The present invention provides a process for preparing compounds of the formula I 
in which R1 is hydrogen, an aliphatic group having 1-8 carbon atoms, C1-C6-alkoxycarbonyl, C1-C6-alkylthiocarbonyl or a cyclic ring system having 3-14 ring atoms, and
R2 is hydrogen, an aliphatic group having 1-8 carbon atoms, or
R1 and R2 together with the carbon atom to which they are bound form a cyclic or bicyclic ring system having 3-14 ring atoms,
comprising the preparation of compounds of the formula II 
xe2x80x83in which R3 and R4 are readily detachable groups and R1 and R2 are as defined above, as starting materials or intermediates and cyclization of these under suitable reaction conditions to give compounds of the formula I.
The process of the present invention makes it possible to prepare compounds of the formula I in a high yield. The cyclization proceeds in yields of at least 80%, in the case of less bulky radicals R at least 90%. Less bulky radicals are, in particular, those in which the group xe2x80x94CHR1R2 is a group having 1-6 carbon atoms. Another advantage is that diacylhydrazines of the formula II can be converted into the I-substituted 5-hydroxypyrazoles of the formula I under particularly convenient conditions, for example short reaction times. The cyclization is preferably catalyzed by acids or bases. A further advantage is that the starting compounds required for the synthesis are readily available and inexpensive. Additional advantages are that the compounds of the formula II are obtained in high purity and that the hydroxypyrazoles of the formula I can be obtained in free form, i.e. essentially free of acid addition salts. In the previously known syntheses, the hydroxypyrazoles were virtually always formed as their acid addition salts, e.g. hydrochlorides, which had to be converted into the free hydroxypyrazoles in an additional work-up step. In the synthesis according to the present invention, on the other hand, the hydroxypyrazoles are obtained directly in the form of the free base which is essentially free of acid addition salts. A further advantage of the process of the present invention is that the 3-hydroxypyrazoles are obtained regioselectively. The proportion of 3-hydroxypyrazoles is low. The yield of 5-hydroxypyrazoles in the synthesis according to the present invention is therefore higher than in the known methods of preparation. Owing to the relatively small amounts in which by-products such as 5-hydroxypyrazoles are formed, a more economical process for preparing the 5-hydroxypyrazoles can thus be carried out.
The diacylhydrazines of the formula II are prepared, for example, by reacting compounds of the formula III 
with activated alkenylcarboxylic acid derivatives of the formula IV 
where R3 and R4 are readily detachable groups and X is a suitable leaving group, with elimination of HX and subsequent isolation of compounds of the formula II: 
For the reaction of III with IV, it is advantageous to use MTBE as solvent and triethylamine as base.
Compounds of the formula III are obtained, for example, by reaction of compounds of the formula V 
with compounds of the formula VI 
and subsequent catalytic hydrogenation of the intermediate N-acylhydrazones of the formula VII 
to give the compounds of the formula III. As catalysts in the catalytic hydrogenation, use is made of Raney-nickel, Pd, Pt or Adams catalysts.
The resulting compounds of the formula III can either be isolated and subsequently reacted with the activated alkenylcarboxylic acid derivatives of the formula IV or be advantageously reacted directly in the reaction solution with the compounds of the formula IV. In the latter case, purification of the intermediates III can be omitted. The reaction conditions for the hydrogenation are described in more detail in the literature, e.g. when using H2/nickel catalysts: DE 1003215; H2/Ray-Ni: OD 84-007127/02; using H2/PtO2: Acta. Chem. Scand. 1967, 21, 2363-2366; using H2/Pt: Ann. Chimica 1968, 58, 1336-1353; using H2/Pd: Indian J. Chem. 1964, 10, 423-424.)
The cyclization of compounds of the formula II is carried out in the presence of acid or base catalysts, with the group R3 on the terminal nitrogen atom and the group R4 being eliminated at the same time. The cyclization is preferably carried out using mineral acids such as hydrochloric acid or sulfuric acid.
The process of the present invention for preparing compounds of the formula I can be summarized by means of the following reaction scheme, where, for example, R1 is an alkyl group, R2 is hydrogen, R3 is the group H3C-CO- and R4 is an alkoxy group: 
The yield in the addition of ketones or aldehydes of the formula VI onto hydrazines of the formula V and the subsequent hydrogenation is in each case at least 80%, frequently in the range from 85 to 90%. The acylation of compounds of the formula III to form compounds of the formula II proceeds in a yield of at least 80%, in the above case in the range from 80 to 90%.
In the definition of the various radicals in the formulae, the terms employed, either on their own (e.g. xe2x80x9cC1-C6-alkylxe2x80x9d) or as parts of or in combination with other chemical groups (e.g. halo-xe2x80x9cC1-C6-alkylxe2x80x9d, etc.), essentially serve as a collective term for a group of compounds. If some of the abovementioned radicals bear one or more substituents, the substituents can in principle be identical or different. Specific meanings of the terms used are:
Aliphatic groups: straight-chain or branched alkyl, alkenyl or alkynyl having in each case up to 8 carbon atoms, where these groups may be substituted by one or more halogen atoms, halo-C1-C6-alkyl groups, C1-C6-alkoxy or aryloxy. Aryloxy is preferably the phenoxy or benzyloxy group.
Alkyl: straight-chain or branched alkyl groups having 1-6, preferably 1-4 carbon atoms, for example the following groups: methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl; pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-3-methylpropyl.
Alkenyl: straight-chain or branched alkenyl groups having 2-6, preferably 2-4 carbon atoms, for example the following groups: ethylene, prop-1-en-1-yl, prop-2-en-1-yl, 1-methylethenyl, buten-1-yl, buten-2-yl, buten-3-yl, 1-methylprop-1-en-1-yl, 2-methylprop-1-en-1-yl, 1-methylprop-2-en-1-yl and 2-methylprop2-en-1-yl, penten-1-yl, penten-2-yl, penten-3-yl, penten-4-yl, 1-methylbut-1-en-1-yl, 2-methylbut-1-en-1-yl, 3-methylbut-1-en-1-yl, 1-methylbut-2-en-1-yl, 2-methylbut-2-en-1-yl, 3-methylbut-2-en-1-yl, 1-methylbut-3-en-1-yl, 2-methylbut-3-en-1-yl, 3-methylbut-3-en-1-yl, 1,1-dimethylprop-2-en-1-yl, 1,2-dimethyl-prop-1-en-1-yl, 1,2-dimethylprop-2-en-1-yl, 1-ethylprop-1-en-2-yl, 1-ethylprop-2-en-1-yl, hex-1-en-1-yl, hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl, 1-methylpent-1-en-1-yl, 2-methylpent-1-en-1-yl, 3-methylpent-1-en-1-yl, 4-methylpent-1-en-1-yl, 1-methylpent-2-en-1-yl, 2-methylpent-2-en-1-yl, 3-methylpent-2-en-1-yl, 4-methylpent-2-en-1-yl, 1-methylpent-3-en-1-yl, 2-methylpent-3-en-1-yl, 3-methylpent-3-en-1-yl, 4-methylpent-3-en-1-yl, 1-methylpent-4-en-1-yl, 2-methylpent-4-en-1-yl, 3-methylpent-4-en-1-yl, 4-methylpent-4-en-1-yl, 1,1-dimethylbut-2-en-1-yl, 1,1-dimethylbut-3-en-1-yl, 1,2-dimethylbut-1-en-1-yl, 1,2-dimethylbut-2-en-1-yl, 1,2-dimethylbut-3-en-1-yl, 1,3-dimetylbut-1-en-1-yl, 1,3-dimethylbut-2-en-1-yl, 1,3-dimetylbut-3-en-1-yl, 2,2-dimethylbut-3-en-1-yl, 2,3-dimetylbut-1-en-1-yl, 2,3-dimethylbut-2-en-1-yl, 2,3-dimethylbut-3-en-1-yl, 3,3-dimethylbut-1-en-1-yl, 3,3-dimethylbut-2-en-1-yl, 1-ethylbut-1-en-1-yl, 1-ethylbut-2-en-1-yl, 1-ethylbut-3-en-1-yl, 2-ethylbut-1-en-1-yl, 2-ethylbut-2-en-1-yl, 2-ethylbut-3-en-1-yl, 1,1,2-trimethylprop-2-en-1-yl, 1-ethyl-1-methylprop-2-en-1-yl, 1-ethyl-2-methylprop-1-en-1-yl and 1-ethyl-2-methylprop-2-en-1-yl.
Alkynyl: straight-chain or branched alkynyl groups having 2-6, preferably 2-4, carbon atoms, for example the following groups: ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, 1-methylethynyl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 1-methylprop-1-yn-1-yl, 2-methylprop-1-yn-1-yl, 1-methylprop-2-yn-1-yl and 2-methylprop-2-yn-1-yl, pentyn-1-yl, pentyn-2-yl, pentyn-3-yl, pentyn-4-yl, 1-methylbut-1-yn-1-yl, 2-methylbut-1-yn-1-yl, 3-methylbut-1-yn-1-yl, 1-methylbut-2-yn-1-yl.
Alkoxy: straight-chain or branched alkoxy groups having 1-6, preferably 2-4, carbon atoms, for example methoxy, ethoxy, isopropyloxy, 2-methylbut-1-yloxy.
Haloalkyl: alkyl groups as mentioned above which are substituted by from 1 to 3 halogen atoms, for example trifluoromethyl, difluoromethyl, dichloromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl.
Halogen: fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
Cyclic ring system: a monocyclic ring system having 3-14, preferably 3-8, ring atoms, where the ring atoms can be carbon, nitrogen or sulfur. Carbocyclic ring systems preferably have 3-8 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The cyclic ring systems can also have one or more double bonds (C3-C8-cycloalkenyl groups). Aromatic ring systems are, in particular, phenyl and naphthyl. If the cyclic ring systems are heterocyclic ring systems, one, two or three carbon atoms can be replaced by heteroatoms, e.g. O, N, S. In principle, the cyclic ring systems can be aromatic, partially hydrogenated or fully hydrogenated. The cyclic ring systems can also be substituted in any way. Examples of suitable substituents are the following groups: C1-C6-alkyl, halogen, halo-C1-C6-alkyl, amino, hydroxy, oxo, C1-C6-alkylamino, di-C1-C6-alkylamino, sulfhydryl, sulfonyl, C1-C6-alkylsulfonyl, etc.
Bicyclic ring system: a bicyclic ring system having 7-14 ring atoms, preferably 7-10 ring atoms, where the ring atoms may be carbon and one or two nitrogen atoms. The ring systems can also have one or two double bonds. In principle, the ring systems can be monosubstituted or polysubstituted by alkyl, alkoxy, hydroxy, oxo or halogen. Examples are: adamantyl, camphyl, camphenyl, norbornyl.
If R1 and R2 together with the carbon atom to which they are bound form a cyclic ring system, this is one of the abovementioned cyclic systems, preferably C3-C8-cycloalkyl groups such as the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and also their unsaturated derivatives having one, two or three double bonds in the ring system.
If R1 is a cyclic ring system having 3-14 ring atoms, it is preferably one of the following groups: C3-Cl4-cycloalkyl, C3-C14-cycloalkenyl, aromatic groups such as phenyl, naphthyl, and also their partially hydrogenated derivatives.
If the aliphatic radical, in particular an alkyl group, is substituted, preference is given to the following substituents: halogen, C1-C6-alkyl, C1-C6-alkoxycarbonyl. The aliphatic radical can be monosubstituted or polysubstituted. In this context, R1 is preferably: difluoromethyl, trifluoromethyl, ethoxycarbonyl, 1,1-diethoxymethylene, 1,1-dimethoxymethylene.
R2 is preferably a hydrogen atom.
R3 is a group which can be readily detached under acidic or basic conditions or thermally, for example alkylcarbonyl, in particular acetyl, propionyl, butyryl, preferably acetyl.
R4 is likewise a group which can readily be detached under acidic or basic conditions or thermally, for example alkoxy, in particular 2-methylprop-1-yloxy (xe2x80x94Oxe2x80x94CH2xe2x80x94CH(CH3)2).
The present invention also provides novel compounds of the formula I which are essentially free of acid addition salts. It also provides compounds of the formula I in which R1 is preferably C4-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxycarbonyl or C1-C6-alkylthiocarbonyl. These compounds are valuable starting materials for preparing further chemical compounds containing a hydroxypyrazole radical, for example compounds having a herbicidal action, as already mentioned at the outset.
The process of the present invention is particularly suitable for the preparation of compounds of the formula I in which the following radicals, either alone or in each case in combination with one another, have the following meanings:
1. R1 and R2 together form a bicyclic ring system, especially adamantyl, norbornyl, camphyl.
3. R1: hydrogen; alkyl; alkyl which is monosubstituted or disubstituted by alkoxy; phenyl; haloalkyl; alkoxycarbonyl. In this context, R1 is preferably: methyl, ethyl, n-propyl, i-propyl; diethoxymethyl, 2,2-diethoxyeth-1-yl; trifluoromethyl; methoxycarbonyl, ethoxycarbonyl.
4. R2: hydrogen, alkyl.
The present invention additionally provides novel compounds of the formula II (diacylhydrazines) which can be used as intermediates. Here, the group xe2x80x94CHR1R2 has the abovementioned meanings. R1 is, in particular, hydrogen, an aliphatic group having 1-8 carbon atoms, C1-C6-alkoxycarbonyl, C1-C6-alkylthiocarbonyl or a cyclic ring system having 3-14 ring atoms. R2 is in particular hydrogen. R1 and R2 may also, according to the present invention, together form a cycloalkyl group or a bicyclic ring system in the above-defined sense.
The following table shows novel intermediates of the formula II which can be prepared by the methods described in the examples:
The invention also provides compounds of the formula III (hydrazines) which can be used as intermediates. Here, the group xe2x80x94CHR1R2 is as defined above. R1 is, in particular, hydrogen, an aliphatic group having 1-8 carbon atoms which may bear one or more halogen atoms or C1-C6-alkoxy groups as substituents, C1-C6-alkoxycarbonyl, C1-C6-alkylthiocarbonyl or a cyclic ring system having 3-14 ring atoms. In particular, R1 is trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, dimethoxymethyl, diethoxymethyl, 2,2-dimethoxyethyl or 2,2-diethoxyethyl.
The following table shows novel intermediates of the formula III which can be prepared by methods analogous to those described in the examples: